The ALL1/MLL gene human homologue of Drosphila TRXwas previously cloned by us by virtue of its rearrangement in infant and therapy-related acute leukemia, resulting in fusion of the gene to a variety of partner genes, or in partial tandem duplication (self fusion). The ensuing fusion genes encode chimeric ALL1 proteins which directly trigger the disease. The normal ALL1 protein was shown by us to be a histone H3-lysine 4 methyltransferase which binds to its target genes to activate their expression. This proposal is based on our recent studies suggesting co-recruitment of the normal partner proteins with ALL1 fusions, identification of primary targets of ALL1 fusions, demonstrating that the UTX H3K27me3 demethylase acts in upregulation of /-/ox genes, and showing that ASH 1, like ALL1, is an H3K4 methytransferase and shares with ALL1 all targets examined. The main directions proposed will be to inquire whether the normal AF4/ENL/AF9 transeriptional elongation complex is co-recruited with all and/or some ALL1 fusions, to apply the new methodology of ChlPSeq for identification and comparison of ALL1 fusions and ALL1 targets, to check selected ALL1 fusions' targets for direct role in leukemogenicity, to examine whether H3K27me3 demethylases have a role in modulating (Hox) expression in hematopoietic cells, including those producing ALL1 fusions, further investigate function of ASH1 compared to ALL1, and ascertain whether ALL1 and not H3K4me3 is the carrier of epigenetic inheritance.